Varieties of chronic hepatitis are a significant cause of morbidity and mortality. The pathogenesis of hepatitis involves death of liver cells (hepatocytes) and fibrosis (cirrhosis). Chronic hepatitis can be caused by persistent infection with a virus such as hepatitis B virus (HBV) or hepatitis C virus (HCV), and may also involve autoimmune processes. The involvement of immunopathology in some forms of hepatitis has led to the treatment of chronic hepatitis conditions with glucocorticoids and immunosuppressive drugs, including azathioprine, cyclosporine and methotrexate. However, these compounds have undesirable side effects and are limited in therapeutic efficacy.
Chronic HBV infections have been treated with interferon. However, this treatment produces limiting side effects and induces prolonged suppression of HBV replication in only about 25% of patients. Nucleoside analogs have also been used to suppress the replication of HBV, but can have severe side effects. In the case of treatment with glucocorticoids, it has been found that the inhibition of the immune response can lead to an elevated level of replication of HBV, augmenting the spread of virus and increasing the risk of developing hepatocellular carcinoma. Moreover, prolonged use of glucocorticoids is associated with metabolic bone disease.
Accordingly, there is need for better therapeutic drugs for treating HBV infection. Ideally, such a drug will be effective to inhibit viral replication in hepatocytes. In addition, the drug should be amenable to delivery by a variety of routes, including oral administration. The drug should also have a long shelf life to allow for shipping and storage. It would also be desirable for such a drug to have anti-replicative activity as well as an ability to inhibit the immune response.